CDK8 is a part of the 30+ protein Mediator complex, that bridges specific transcription factors with the general transcription machinery & RNA pol II. The CDK8 module consists of 4 proteins: CDK8, CyclinC, MED12, and MED13. MED12 and CyclinC are required for CDK8 kinase activity; MED13 is required to recruit the module to the small Mediator complex. The role of CDK8 on transcription is context-specific, depending on the specific biological context and the identity of the transcription factors with which it interacts. The role of CDK8 on transcription is context-specific, depending on the specific biological context and the identity of the transcription factors with which it interacts.
CDK8 expression is upregulated in tumors. CDK8 regulates β-catenin signaling, upregulated in many tumor types, including, but not limited to Colorectal (47-76%), gastric, pancreatic, and mH2A-deficient melanoma. CDK8 overexpression also has correlated with poor outcomes in colon-specific cancer, gastric cancer, breast cancer and, ovarian cancer. Correlation in CDK8 expression and disease states such as colon cancer, gastric cancer, colorectal cancer, ovarian cancer and melanoma. Dale et al. Nature Chemical Biology (Oct. 26, 2016), DOI: 10.1038/NCHEMBIO. 1952. CDK8 expression is also observed in breast cancer. Mallinger et al., Journal of Medicinal Chemistry (1980) DOI: 10.1021/acs.jmedchem. 5b01685.
It was found that CDK8 inhibitors were active against AML cell characterized by significantly higher levels of STAT5 S726 and STAT1 S727, and that this founding provides a rationale for the clinical development of CDK8 inhibitors as a personal therapeutic approach in AML. Rzymski et al. Oncotarget. 2017 May 16; 8(20): 33779-33795.
CDK8 has been identified as a negative regulator of IL-10 production during innate immune activation that suggests CDK8 inhibitors may warrant consideration as therapeutic agents for inflammatory disorders. Johannessen et al. Published Online: 14 Aug. 2017; DOI: 10.1038/NCHEMBIO.2458 Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells.
Aberrant expression of CDK8 is also associated with the regulation of malignant phenotype and with poor prognosis in human laryngeal squamous cell carcinoma. MingHua Li et al. Eur Arch Otorhinolaryngol (Feb. 20, 2017).
CDK8 also mediates immune surveillance of tumors. CDK8 directly phosphorylates serine 727 on STAT1 downstream of cytokine (e.g. IFNg) stimulation, constitutive in natural killer (NK cells). Inhibition of STAT1 phosphorylation in NK cells results in increased NK cell cytotoxicity towards tumor cells in vitro and in vivo, and thus, CDK8 may be helpful for the treatment of cancers associated with increased NK cell cytotoxicity, including, but not limited to lung cancer and lung cancer metastasis, breast cancer and breast cancer metastasis, and leukemia. CDK8 may also increase the effectiveness of chemotherapeutic agents.
Dysregulation of CDKs has been linked to pathological events and both proliferative and non-proliferative disease, including cancers, Alzheimer's disease (AD), Parkinson's disease, Stroke/ischemia, pain, traumatic brain injury, kidney disease, inflammation pathologies, type 2 diabetes, and various viral infections (HSV, HCMV, HPV, HIV).
Currently, there are no FDA approved CDK8 inhibitors. Accordingly, there is a substantial unmet need for novel CDK8 inhibitors.